Cognitive decline and dementia are major health concerns in the elderly. These conditions are a major source of morbidity and health care burden in nursing homes that significantly affect patients' quality of life. There is accumulating evidence that anticholinergic medications are associated with significant central adverse effects including cognitive impairment and dementia in the elderly. The extent of the adverse effect may vary with the level of anticholinergic activity of these medications. Furthermore, underlying diseases like depression can make the elderly more susceptible to centrally mediated effects of anticholinergics due to significant cognitive deficits associated with the disease. Despite significant use of anticholinergic medications in the elderly nursing home residents, little is known about the cognitive impact of these agents in the elderly with depression. Using the previously validated Anticholinergic Drug Scale (ADS), the proposed study will evaluate the central adverse effects profile of medications with significant anticholinergic activity in the eldrly residents with depression. The aims of the proposed research are to: (1) examine the risk of dementia associated with clinically significant anticholinergics in the elderly residents with depression, (2) assess the impact of clinically significant anticholinergics on cognitive performance in the elderly residents with depression, and (3) evaluate other central adverse effects of clinically significant anticholinergics in the elderly residents with depression. Anticholinergic medication exposure will be classified based on the four levels of anticholinergic activity (0 to 3) of ADS, with a focus on clinically significant, high level (2 and 3) anticholinerics. The following hypotheses will be tested among elderly residents with depression that: (i) there is greater risk for dementia among high-level (level 2 or 3) anticholinergic users than low-level (level 1) users; (ii) there is greater decline in cognitive performance among high-level anticholinergics users than low-level users; and (iii) there is greater risk for falls/fractures an all-cause mortality among high-level anticholinergics than low-level users. A retrospective design involving large national cohorts of elderly nursing home residents > 65 years will be used to test the study hypotheses. Clinically rich Minimum Data Set (MDS) linked Medicare claims data involving Parts A, B, and D will be used to address the research objectives. The measures of adverse effects will include mild cognitive performance, dementia, falls/fractures, and all-cause mortality captured in Medicare and MDS datasets. The study will involve a multiple propensity score approach to adjust for the selection bias across anticholinergic levels within the multivariate context of the Andersen Behavioral Model. Propensity score adjusted multivariate analyses including Cox models will be used to evaluate the safety profile of anticholinergics. The proposed investigation will provide a strong evidence base regarding central adverse effects profile of anticholinergics and thereby help to optimize anticholinergic use and strengthen the ADS as a quality of care measure for depression in nursing homes. PUBLIC HEALTH RELEVANCE: Despite significant use of anticholinergic medications in elderly nursing home residents, little is known about the adverse effects profile of these agents in the elderly with depression. The proposed investigation will provide a strong evidence base for central adverse effects of anticholinergics and strengthen support for the Anticholinergic Drug Scale as a quality of care measure in long term care. In addition, the findings will be beneficial to health care providers and policy makers to optimize anticholinergic medication use in the elderly and will be instrumental in improving the quality of care in this vulnerable population